We found that null mutations in the gene encoding the secreted growth factor progranulin (PGRN) are a frequent cause of frontotemporal dementia, particularly in patients affected with the pathological subtype referred to as frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Subsequently, the major protein that makes up the inclusions found in FTLD-U (and in amyotrophic lateral sclerosis, ALS) was identified as TAR DNA-binding protein-43 (TDP-43), an obscure nuclear protein known to be involved in exon splicing. Subsequent to this finding, mutations in the gene encoding TDP-43 (TARDBP) were identified as a direct cause of neurodegeneration in sporadic and familial patients with ALS. We have shown that decreasing PGRN expression activates cell death pathways leading to pathological processing of TDP-43 by caspases in cell culture models. Recent preliminary data revealed that deletion of progranulin in mice and in knockdown experiments in cells lead to enhanced sensitivity to ER stressors and increased levels of the transcription factor CHOP (C/EBP homologous protein), a protein that is induced by ER stress and promotes apoptosis. Without PGRN or in the presence of mutations in TARDBP, TDP-43 gets cleaved, which leads to translocation from the nucleus to the cytosol, a pathologic phenotype which resembles what happens to TDP-43 in patients with FTLD-U or ALS. Thus, loss of TDP-43 function due to inappropriate cleavage, translocation, or inclusion formation could play an important role in neurodegeneration. We also hypothesize that PGRN mutations other than null mutations, such as missense mutations, or causal TARDBP mutations can sufficiently abolish PGRN and TDP-43 functions to cause neurodegeneration. The overall goals of our proposal are 1) to provide additional mechanistic insight into the signaling pathways associated with PGRN and neuronal survival 2) to determine whether the shorter TDP-43 fragments are more fibrillogenic and are neurotoxic, a property that would explain the formation of inclusions, redistribution and neurodegeneration seen in FTLD-U and ALS; and 3) to explore neurodegenerative disease mechanism associated with TARDBP mutations. Our hypothesis is that loss of functional PGRN leads to loss of functional TDP-43, which leads to cell death. PUBLIC HEALTH RELEVANCE: This proposal is designed to further investigate how progranulin is involved in the processing and biological function of TDP-43 and to determine if PGRN mutations other than null mutations are pathogenic. We will study the mechanism underlying TDP-43-associated neuropathology and determine whether mutations in TDP-43 can directly cause human diseases. Our goal is to gain better understanding of the underlying biology and developing insights causing TDP-43 proteinopathies, which might ultimately lead to improved therapies.